(+)-Pilocarpine, the most important imidazole alkaloid, has been for many years the focus of much attention because of its extensive pharmacological properties. These include diaphoretic effects, stimulation of the parasympathetic system, miotic action, and particularly applications in ophthalmology. Pilocarpine is currently the drug of choice for treatment of narrow and wide angle glaucoma because it decreases the intraocular pressure and can be administered for long periods without side effects. Pilocarpine along with its epimer isopilocarpine was first isolated in 1875 from various species of Pilocarpus plants belonging to the Rutaceae family. The structure and stereochemistry of this alkaloid, proposed in 1900, was later confirmed in degradation studies, X-ray analysis, and several syntheses.
Earlier syntheses of (+)-pilocarpine were based on the formation of the lactone ring at an early stage followed by various group transformation and construction of the imidazole ring in the final stages. These syntheses suffered from the burden of many steps, low yields, lack of stereoselectivity, and mixtures of N-methylimidazole regiosiomers. A later approach to (+)-pilocarpine was based on using a preformed imidazole nucleus and building the lactone at a subsequent stage. However, the reported yield was less than 1%. Link, Helv. Chim. Acta 55, 1053 (1972). More recently a synthesis of (+)-pilocarpine starting with L-histidine was reported. Noordam, Rec. J.R. Neth. Chem. Soc., 100, 441 (1981). This synthesis is based on regioselective methylation of L-histidine, alkylation of the a-carbon with an ethyl malonate, and decarboxylation and formation of the lactone. In this last route the alkylation and decarboxylation steps occurred with limited stereochemical control, resulting in a mixture of diastereoisomeric products.
A chirospecific synthesis of (+)-pilocarpine using D-methionine or D-2-aminobutanol as chiral educt has been reported. Compagnone and Rapoport, J. Org. Chem., 51:10, 1713 (1986). However, the yield is reduced because (+)-pilocarpine is obtained through epimerization of (+)-isopilocarpine, and the epimer mixture must be separated.
J. Wolf and H. Rapoport describe the synthesis of certain dipeptide analogues starting from L-aspartic acid in the Journal of Organic Chemistry, 54, 3164-3173 (1989). However, the compound they describe as compound 28 (which is of interest for the present invention) gave the desired diastereomer in a ratio of 3.5:1 (with a yield of 78%) and included several impurities that had to be separated. Such a diastereomer ratio is impractically low for use in a commercially acceptable synthesis towards (+)-pilocarpine or its analogues.
An analogue of (+)-pilocarpine, (2)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl]-2-oxazolidinone, is described in U.S. Pat. No. 4,977,172, issued Dec. 11, 1990, which describes use of said pilocarpine analogue for treating the symptoms of cognitive decline in an elderly patient (e.g. Alzheimer's disease). This analogue is not formed from an L-aspartic acid precursor.